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Chronic myeloproliferative neoplasms

High rate of recurrent venous thromboembolism in patients with myeloproliferative neoplasms and effect of prophylaxis with vitamin K antagonists

Leukemia volume 30, pages 2032–2038 (2016)Cite this article

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Abstract

The optimal duration of treatment with vitamin K antagonists (VKA) after venous thromboembolism (VTE) in patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) is uncertain. To tackle this issue, we retrospectively studied 206 patients with MPN-related VTE (deep venous thrombosis of the legs and/or pulmonary embolism). After this index event, we recorded over 695 pt-years 45 recurrences, venous in 36 cases, with an incidence rate (IR) of 6.5 per 100 pt-years (95% confidence interval (CI): 4.9–8.6). One hundred fifty-five patients received VKA; the IR of recurrent thrombosis per 100 pt-years was 4.7 (95% CI: 2.8–7.3) on VKA and 8.9 (95% CI: 5.7–13.2) off VKA (P=0.03). In patients receiving VKA, the IR of recurrent thrombosis per 100 pt-years was 5.3 (95% CI: 3.2–8.4) among 108 patients on long-term VKA and 12.8 (95% CI: 7.3–20.7) after discontinuation among the 47 who ceased treatment (P=0.008), with a doubled risk of recurrence after stopping VKA (hazard ratio: 2.21, 95% CI: 1.19–5.30). The IR of major bleeding per 100 pt-years was 2.4 (95%: CI: 1.1–4.5) on VKA and 0.7 (95% CI: 0.08–2.5) off VKA (P=0.08). In conclusion, in MPN patients with VTE recurrent thrombosis is significantly reduced by VKA and caution should be adopted in discontinuation; however, the incidence of recurrence on treatment remains high, calling for clinical trials aimed to improve prophylaxis in this setting.

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References

  1. Patrono C, Rocca B, De Stefano V . Platelet activation and inhibition in polycythemia vera and essential thrombocythemia. Blood 2013; 121: 1701–1711.

    Article  CAS  PubMed  Google Scholar 

  2. Landolfi R, Marchioli R, Kutti J, Gisslinger H, Tognoni G, Patrono C et al. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 2004; 350: 114–124.

    Article  CAS  PubMed  Google Scholar 

  3. Marchioli R, Finazzi G, Landolfi R, Kutti J, Gisslinger H, Patrono C et al. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol 2005; 23: 2224–2232.

    Article  PubMed  Google Scholar 

  4. Marchioli R, Finazzi G, Specchia G, Cacciola R, Cavazzina R, Cilloni D et al. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med 2013; 368: 22–33.

    Article  CAS  PubMed  Google Scholar 

  5. Harrison CN, Campbell PJ, Buck G, Wheatley K, East CL, Bareford D et al. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med 2005; 353: 33–45.

    Article  CAS  PubMed  Google Scholar 

  6. Gisslinger H, Gotic M, Holowiecki J, Penka M, Thiele J, Kvasnicka HM et al. Anagrelide compared with hydroxyurea in WHO- classified essential thrombocythemia: the ANAHYDRET Study, a randomized controlled trial. Blood 2013; 121: 1720–1728.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Goldhaber SZ . Venous thromboembolism: epidemiology and magnitude of the problem. Best Pract Res Clin Haematol 2012; 25: 235–242.

    Article  PubMed  Google Scholar 

  8. De Stefano V, Za T, Rossi E, Vannucchi AM, Ruggeri M, Elli E et al. Recurrent thrombosis in patients with polycythemia vera and essential thrombocythemia: incidence, risk factors, and effect of treatments. Haematologica 2008; 93: 372–380.

    Article  CAS  PubMed  Google Scholar 

  9. Hernández-Boluda JC, Arellano-Rodrigo E, Cervantes F, Alvarez-Larrán A, Gómez M, Barba P et al. Oral anticoagulation to prevent thrombosis recurrence in polycythemia vera and essential thrombocythemia. Ann Hematol 2015; 94: 911–918.

    Article  PubMed  Google Scholar 

  10. Barbui T, Barosi G, Birgegard G, Cervantes F, Finazzi G, Griesshammer M et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol 2011; 29: 761–770.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Kreher S, Ochsenreither S, Trappe RU, Pabinger I, Bergmann F, Petrides PE et al. Prophylaxis and management of venous thromboembolism in patients with myeloproliferative neoplasms: consensus statement of the Haemostasis Working Party of the German Society of Hematology and Oncology (DGHO), the Austrian Society of Hematology and Oncology (ÖGHO) and Society of Thrombosis and Haemostasis Research (GTH e.V.). Ann Hematol 2014; 93: 1953–1963.

    Article  CAS  PubMed  Google Scholar 

  12. Tefferi A, Barbui T . Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk-stratification and management. Am J Hematol 2015; 90: 162–173.

    Article  CAS  PubMed  Google Scholar 

  13. Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2 Suppl): e419S–e4194.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ellis MH, Lavi N, Vannucchi A, Harrison C . Treatment of thromboembolic events coincident with the diagnosis of myeloproliferative neoplasms: a physician survey. Thromb Res 2014; 134: 251–254.

    Article  CAS  PubMed  Google Scholar 

  15. Tefferi A, Vardiman JW . Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia 2008; 22: 14–22.

    Article  CAS  PubMed  Google Scholar 

  16. Schulman S, Kearon C Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3: 692–694.

    Article  CAS  PubMed  Google Scholar 

  17. Boutitie F, Pinede L, Schulman S, Agnelli G, Raskob G, Julian J et al. Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants' data from seven trials. BMJ 2011; 342: d3036.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Prandoni P, Noventa F, Ghirarduzzi A, Pengo V, Bernardi E, Pesavento R et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica 2007; 92: 199–205.

    Article  PubMed  Google Scholar 

  19. van Es N, Coppens M, Schulman S, Middeldorp S, Büller HR . Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood 2014; 124: 1968–1975.

    Article  CAS  PubMed  Google Scholar 

  20. Prandoni P . Links between arterial and venous disease. J Intern Med 2007; 262: 341–350.

    Article  CAS  PubMed  Google Scholar 

  21. EINSTEIN Investigators EINSTEIN Investigators Bauersachs R EINSTEIN Investigators Berkowitz SD EINSTEIN Investigators Brenner B EINSTEIN Investigators Buller HR EINSTEIN Investigators Decousus H EINSTEIN Investigators Gallus AS et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363: 2499–2510.

    Article  Google Scholar 

  22. EINSTEIN–PE Investigators EINSTEIN–PE Investigators Büller HR EINSTEIN–PE Investigators Prins MH EINSTEIN–PE Investigators Lensin AW EINSTEIN–PE Investigators Decousus H EINSTEIN–PE Investigators Jacobson BF EINSTEIN–PE Investigators Minar E et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366: 1287–1297.

    Article  Google Scholar 

  23. Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013; 369: 799–808.

    Article  CAS  PubMed  Google Scholar 

  24. Hokusai-VTE Investigators Hokusai-VTE Investigators Büller HR Hokusai-VTE Investigators Décousus H Hokusai-VTE Investigators Grosso MA Hokusai-VTE Investigators Mercuri M Hokusai-VTE Investigators Middeldorp S Hokusai-VTE Investigators Prins MH et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369: 1406–1415.

    Article  Google Scholar 

  25. Paul A Kyrle . How I manage recurrent deep-vein thrombosis. Blood 2015; 27: 696–702.

    Google Scholar 

  26. Oger E . Incidence of venous thromboembolism: a community-based study in Western France EPI-GETBP Study Group. Groupe d'Etude de la Thrombose de Bretagne Occidentale. Thromb Haemost 2000; 83: 657–660.

    Article  CAS  PubMed  Google Scholar 

  27. Naess IA, Christiansen SC, Romundstad P, Cannegieter SC, Rosendaal FR, Hammerstrøm J . Incidence and mortality of venous thrombosis: a population-based study. J Thromb Haemost 2007; 5: 692–699.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

TB and AMV were supported by a grant from Associazione Italiana per la Ricerca sul Cancro (AIRC, Milano) 'Special Program Molecular Clinical Oncology 5 × 1000' to AGIMM (AIRC-Gruppo Italiano Malattie Mieloproliferative). VDS was supported by an unrestricted grant from Bruno Farmaceutici Foundation.

Author information

Author notes

  1. V De Stefano and T Barbui: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Hematology, Catholic University, Roma, Italy

    V De Stefano, E Rossi & S Betti

  2. Ospedale San Bortolo, Vicenza, Italy

    M Ruggeri & I Nichele

  3. Hospital Clínic, IDIBAPS, Barcelona, Spain

    F Cervantes

  4. Hematology Department, Hospital del Mar, Barcelona, Spain

    A Alvarez-Larrán

  5. Oncohematology Division, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milano, Italy

    A Iurlo & D Cattaneo

  6. A.O. Universitaria, Padova, Italy

    M L Randi

  7. Hematology Division, A.O. San Gerardo, Monza, Italy

    E Elli

  8. Hematology Division, A.O. Papa Giovanni XXIII, Bergamo, Italy

    M C Finazzi & G Finazzi

  9. Department of Hematology and Vascular Disorders, Skane University Hospital, Lund, Sweden

    E Zetterberg

  10. Università di Bologna, Bologna, Italy

    N Vianelli

  11. Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy

    G Gaidano

  12. University Hospital of Olomouc, Olomouc, Czech Republic

    M Palova

  13. Meir Medical Center, Hematology Institute, Kefar Sava, Israel

    M H Ellis

  14. A.O. Universitaria, Catania, Italy

    R Cacciola

  15. Arcispedale Santa Maria Nuova - IRCCS, Reggio Emilia, Italy

    A Tieghi

  16. Hospital Clinico, Valencia, Spain

    J C Hernandez-Boluda

  17. A.O. Ospedale Niguarda Ca’ Granda, Milano, Italy

    E Pungolino

  18. A.O. Universitaria, Bari, Italy

    G Specchia

  19. A.O. Santa Croce e Carle, Cuneo, Italy

    D Rapezzi

  20. IRCCS Ospedale San Raffaele, Milano, Italy

    A Forcina

  21. A.O. Universitaria, Messina, Italy

    C Musolino

  22. FROM Research Foundation, A.O. Papa Giovanni XXIII, Bergamo, Italy

    A Carobbio & T Barbui

  23. J. W. Klinikum, Minden, Germany

    M Griesshammer

  24. Center for Research and Innovation of Myeloproliferative Neoplasms, A.O.U. Careggi, University of Florence, Firenze, Italy

    E Sant’Antonio & A M Vannucchi

Authors
  1. V De Stefano
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  2. M Ruggeri
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  15. I Nichele
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  16. D Cattaneo
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  18. M H Ellis
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  30. A M Vannucchi
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  31. T Barbui
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Corresponding author

Correspondence to T Barbui.

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De Stefano, V., Ruggeri, M., Cervantes, F. et al. High rate of recurrent venous thromboembolism in patients with myeloproliferative neoplasms and effect of prophylaxis with vitamin K antagonists. Leukemia 30, 2032–2038 (2016). https://doi.org/10.1038/leu.2016.85

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